|Year : 2014 | Volume
| Issue : 1 | Page : 24-33
Nonfluoride remineralization: An evidence-based review of contemporary technologies
Dheeraj D Kalra1, Rinku D Kalra2, Prajna V Kini3, CR Allama Prabhu4
1 Department of Public Health Dentistry, Sinhgad Dental College and Hospital, Pune, Maharashtra, India
2 Department of Oral and Maxillofacial Surgery, Yerala Dental College and Hospital, Navi Mumbai, Maharashtra, India
3 Department of Oral Diagnosis, Medicine and Radiology, Srinivas Institute of Dental Sciences, Mangalore, Karnataka, India
4 Department of Preventive and Community Dentistry, College of Dental Sciences, Davangere, Karnataka, India
|Date of Web Publication||6-May-2015|
Dr. Dheeraj D Kalra
Department of Public Health Dentistry, Sinhgad Dental College and Hospital, Pune, Maharashtra
Source of Support: None, Conflict of Interest: None
Since past few years, there have been many strategies to combat dental caries, erosion, hypersensitivity, and many other oral conditions. The last decade has seen many advanced researches in the field of dentistry. The scope of dentistry has evolved from only a curative one to a largely preventive one. There have been technologies available for the minimal invasive cure of dental caries, early diagnosis and early reversal of the initial carious lesion using nonoperative techniques. There has also more focus being made to treat dental caries as a process rather than curing the lesion only. The role of saliva, demineralization and remineralization has been better understood. The aim of this paper is to review the contemporary nonfluoridated systems available for remineralization therapy and ideas for their implementation into clinical practice. A search of articles from "PubMed" and "Medline" and databases like Google and Google scholar, ScienceDirect and Wiley with the keywords remineralization, demineralization, nonfluoridated demineralizing agents was conducted in the month of August 2012 out of a total 114 articles, 86 articles have been used in the present evidence-based review.
Keywords: Anti-caries agents, demineralization, nonfluoride remineralization technologies, remineralization
|How to cite this article:|
Kalra DD, Kalra RD, Kini PV, Allama Prabhu C R. Nonfluoride remineralization: An evidence-based review of contemporary technologies. J Dent Allied Sci 2014;3:24-33
|How to cite this URL:|
Kalra DD, Kalra RD, Kini PV, Allama Prabhu C R. Nonfluoride remineralization: An evidence-based review of contemporary technologies. J Dent Allied Sci [serial online] 2014 [cited 2018 Sep 19];3:24-33. Available from: http://www.jdas.in/text.asp?2014/3/1/24/156525
| Introduction|| |
Dental caries remains the most common totally preventable disease facing mankind. Its impact ranges from a minor inconvenience requiring surgical caries removal and restorative treatment to excruciating pain and loss of masticatory function.  The term "caries" originates from Latin for "rot" or "rotten" prompted original researchers of the past two centuries to develop methods to counter this process of tooth decay or demineralization. The heart of caries research and prevention lies in the opposition of these terms that is replacement or remineralization. The role of plaque biofilm in caries causation is beyond refute. It is a site of bacterial proliferation and growth, acid/base regulation at the tooth surface and a reservoir for calcium ion exchange between the tooth and the saliva. 
| Critical PH|| |
Stephan demonstrated plaque accumulation following exposure glucose and production of acids within the plaque and subsequent recovery of the plaque pH.  Critical pH is the term given to the highest pH at which there is a net loss of minerals from tooth enamel. The calcium and phosphate ions that are lost from the tooth diffuse out into dental plaque fluid and saliva. If the acid attack is chronic and prolonged, progressively greater amounts of calcium and phosphate minerals, diffuse out of the tooth, causing the crystalline structure of the tooth to shrink in size, while pores enlarge. Eventually, a carious lesion develops. 
| The Protective and Risk Factors|| |
Protective factors are biological or therapeutic factors or measures that can collectively offset the challenge presented by the caries risk factors. The risk factors and protective factors have been depicted in [Figure 1]. 
|Figure 1: Depicts "the caries imbalance". (Adapted from Bernie KM. Remineralization! Strategies!! Advancements in fluoride, calcium and phosphate technologies) to help to remember the imbalance (WREC; BAD; SAFE) words have been used|
Click here to view
The management of a cariogenic biofilm may be looked at in several ways. Three strategies have dominated the history of modern dentistry:
- Plaque elimination/reduction by home care,
- Fermentable carbohydrate reduction or elimination and
- Introduction of fluoride to reduce caries.
Stannous fluoride and amine fluoride as well as numerous metallic ions have demonstrated antimicrobial effectiveness. Essential oils, a mixture of thymol, eucalyptol, methyl salicylate and menthol have been demonstrated to be effective in preventing the build-up of supragingival plaque and gingivitis. Triclosan, chlorhexidine also reduce plaque from the oral cavity. 
| Demineralization and Remineralization|| |
Demineralization begins at the atomic level on the crystal surface inside the enamel or dentin and can continue unless halted with the end point being cavitation. The initial stages of the carious lesion are characterized by a partial dissolution of the tissue, leaving a 2-50-μm thick mineralized surface layer and a subsurface lesion with a mineral loss of 30-50% extending into enamel and dentin. In a clinical examination, the lesion will appear chalky white and softened. In practice, the goal is to stop the process at the white spot lesion stage, when intervention can still be nonsurgical.  If the lesion advances, the outer enamel layer can eventually become cavitated. At this point, the lesion is not reversible and requires operative intervention. Also with the recession of gingival and root exposure and loss of cementum, the cervical areas are more prone to demineralization. 
Over the course of human life, enamel and dentin undergo unlimited cycles of demineralization and remineralization.  Localized acids produced by plaque after a cariogenic challenge, lower the surface pH of the tooth and start diffusing into the tooth, leaching calcium and phosphate from the enamel. At this time, the plaque pH may have dropped to 4.0-4.5. This mineral loss leads to weakening of the mechanical properties and may lead to cavitation.
When oral pH returns to near neutral, Ca 2+ and PO43− ions in saliva incorporate themselves into the depleted mineral layers of enamel as new apatite. The demineralized zones in the crystal lattice act as nucleation sites for new mineral deposition [Figure 2].
This cycle is fundamentally dependent upon enamel solubility and ion gradients.
Theories explaining the phenomenon of subsurface demineralization in enamel are:
- Chemical inhibition of dissolution of the surface enamel by salivary components or fluoride derived from the oral environment.
- Anatomical variations in structure and composition of enamel.
- Chemistry specific to calcium phosphates, such as formation of dicalcium phosphate dihydrate (DCPD) or less soluble subsurface complexes
- A more general phenomenon that may involve coupled diffusion.
The theories are not mutually exclusive, and the relative importance of the proposed factors might vary with clinical and experimental conditions Dowker et al. 
Carious dentin can be classified into the outer caries-infected dentin and inner caries-affected dentin. Unlike caries-infected dentin, collagen fibrils of the caries-affected dentin still show intermolecular cross-links and distinct cross-banding patterns when examined by transmission electron microscopy, and, therefore, are physiologically remineralizable. 
Dentin is composed of about 30 volume % type I collagen fibrils and noncollagenous proteins that form a scaffold reinforced with apatite, which represents 50% of the matrix, with the remainder being fluids.  Apatite in dentin has a much smaller crystallite size, higher carbonate content and is more susceptible to acidic dissolution than enamel apatite. Hence, once the carious process enters the dentin, the demineralization rate is accelerated. Moreover, the high organic content in dentin makes its remineralization a much more complex process than remineralization of the enamel. In dentin, the apatite occurs in two specific regions, within the fibrils (intra-fibrillar mineral) and between fibrils (extra-fibrillar mineral). Primarily the intra-fibrillar mineral, has been suggested to be crucial for the normal mechanical properties of the tissue. Therefore, a critical aspect in treating carious dentin is not only to replace the lost mineral, but principally to provide the tight association of the re-grown mineral with the demineralized matrix thus enabling the recovery of the mechanical properties of the tissue.  Guide tissue remineralization represents a novel strategy in collagen biomineralization. This strategy utilizes nanotechnology and biomimetic principles to achieve intra-fibrillar and extra-fibrillar remineralization of a collagen matrix in the absence of apatite seed crystallites  (this strategy will be covered in detail later).
For remineralization of enamel to occur the following six conditions or events must occur at the same time:
- Sufficient mineral must be present in the saliva.
- A molecule of carbonic acid must be produced.
- The carbonic acid molecule must be produced in proximity to a mineral molecule.
- This all has to occur in proximity to a demineralized spot in the hydroxyapatite (HAP) latticework.
- That spot of the tooth has to be clean, so that the mineral-deficient spot is accessible.
- The carbonic acid must convert to carbon dioxide and water before any of the above circumstances change. 
The role of saliva in maintaining oral health cannot be refuted, as the relationship of hyposalivation and increase in dental caries has already been a proven fact.
Functions of saliva include cleansing, lubrication, mucosal integrity, buffering, remineralization, taste, digestion and bearing anti-microbial properties.  As age progresses, the incidence of root caries also increases. Severity reaches over one lesion by age 50, two lesions by age 70, and just over three lesions for those 75 and older.  Also in patients undergoing radiotherapy of head and neck region, changes in the dentition, saliva, microflora, and diet which are involved in the pathogenesis of radiation caries are observed. Demineralization in irradiated teeth is histologically characterized by total loss of the prismatic structure, decreased mechanical parameters of the enamel. Similarly to enamel caries, dentin radiation caries usually begins with apatite dissolution, hydrogen free radicals and hydrogen peroxide present within the dentin denaturate its organic components and alter dentin micro-hardness. Activation of salivary matrix metalloproteinases plays a role in the pathogenesis of dentin radiation caries. The saliva becomes thicker, leading to difficulties in chewing and speaking, taste loss, and increased caries risk. In the absence of saliva, demineralization is more likely to occur, and it is also more difficult to stop or revert. There is a reduced buffering capacity of saliva. The average postirradiation pH falls from about 7.0 to 5.0, which is definitively cariogenic. Because of the lowered pH and buffering capacity, the minerals of enamel and dentin can easily dissolve. There is a transient high-concentrations of salivary total proteins, IgA, albumin, lactoferrin, lysozyme, hexosamines, salivary peroxidase, and myeloperoxidase. An increase in acidogenic and cariogenic microorganisms (Streptococcus mutans, Lactobacillus, and Candida species), along with a reduction in noncariogenic microorganisms such as Streptococcus sanguis, Neisseria, and Fusobacterium, is seen. 
Dental erosion is a localized loss of the tooth surface by a chemical process of acidic dissolution of nonbacterial origin. The process may be caused by extrinsic or intrinsic agents. Extrinsic agents include acidic foodstuffs, beverages, snacks and following environmental exposure to acidic agents. Intrinsic erosion is associated with gastric acid which may be present intra-orally following vomiting, regurgitation, gastroesophageal reflux.  Dentists may be the first persons to diagnose the possibility of gastroesophageal reflux disease, particularly in the case of "silent refluxers."  Lifestyle changes and a rise in the consumption of acidic foods and beverages have led to an increase in the prevalence of dental erosion around the world in recent years especially in the developed countries. If not regulated, dental erosion could lead to increased sensitivity and loss of tooth if left unchecked. For these reasons, dental erosion is rapidly gaining attention as a leading form of dental decay. 
Why to go for nonfluoride strategies?
- Fluoride is highly effective on smooth-surface caries, but its effect is limited on pit and fissure caries. ,,
- A high-fluoride strategy cannot be followed to avoid the potential for adverse effects (e.g., fluorosis) due to overexposure to fluoride. 
- Toxicity of fluoride increases with inadequate nutrition. 
- Although fluoride has had a profound effect on the level of caries prevalence, it is far from a complete cure. 
- The anti-fluoride lobby which is mounting pressure poses certain legal limitations to the use of fluorides. ,
- Certain countries do not have fluoridated products. 
Ideal requirements of a remineralization material
- Diffuses into the subsurface or delivers calcium and phosphate into the subsurface. 
- Does not deliver an excess of calcium. 
- Does not favor calculus formation. 
- Works at an acidic pH. 
- Works in xerostomic patients. 
- Boosts the remineralizing properties of saliva. 
- For novel materials, shows a benefit over fluoride. 
There are several challenges to establishing the clinical effectiveness of remineralization agents:
- They must demonstrate a benefit over and above an established and highly effective agent, namely, fluoride.
- They must provide a remineralizing benefit in addition to the natural remineralizing properties of saliva. 
- The organic constituents of saliva can serve as accelerators and inhibitors of the remineralization process. Teeth are covered by the acquired pellicle, which has been shown to retard remineralization.
- If sugar-free chewing gum is the delivery vehicle, chewing gum has a major remineralizing effect in and of itself, which makes it more challenging to show an additional benefit when using gum as the delivery vehicle.
- Too much of a good thing could possibly disrupt the mineralization homeostasis of the mouth and favor calculus formation. 
- There may be ingredient compatibility issues. Products are designed to deliver a new agent (i.e., calcium ions) and fluoride simultaneously from single-phase products and may present formulation challenges such as long-term fluoride compatibility. 
- Preclinical models may not necessarily be predictive of clinical performance for these nonfluoride agents and that new agents still require direct clinical validation to ensure efficacy. 
| Methodology|| |
Source of Data
The bulk of this evidence based review will deal with contemporary nonfluoride technologies. A search of articles from "PubMed" and "Medline" and databases like Google and Google scholar, ScienceDirect and Wiley with the keywords remineralization, demineralization, nonfluoridated demineralizing agents was conducted in the month of August 2012. We retrieved a total of 123 abstracts and 157 full-length papers, of which 114 articles that discussed current technologies of nonfluoridated demineralizing agents were read and 86 most relevant articles were included in this paper.
| Nonfluoride Remineralization Strategies|| |
The management of dental caries must be of a preventive rather than just curative approach. However, the word caries is unfortunately used for both the dental caries (and cavities), which occurs in the tooth and the carious process which occurs in the biofilm. The carious lesion can be thought as a reflection of the carious process. Preventive dentistry is all about how we stop the carious process-remineralize the initial noncavitated white spots, alter the metabolism in plaque and control plaque itself.
The following classification will be used for discussing nonfluoride remineralization strategies.
According to the mode of action
- Agents which interact with tooth enamel.
- Those neutralizing the bacterial acid.
- Anti-plaque agents.
A. Agents which interact with tooth enamel
A1. Casein phosphor-peptides-amorphous calcium phosphate
Casein, a bovine milk phosphor-protein is known to interact with calcium and phosphate and is a natural food component. Its technical name is casein phosphor-peptides-amorphous calcium phosphate (CPP-ACP), or CPP-ACP. ,, It was discovered by Prof. Reynolds at the School of Dental Science at the University of Melbourne in Australia.  CPP contain the cluster sequence of -Ser (P)-Ser (P)-Ser (P)-Glu-Glu from casein. , The CPP are produced from a tryptic digest of the milk protein casein, then aggregated with calcium phosphate and purified by ultrafiltration. Under alkaline conditions, the calcium phosphate is present as an alkaline amorphous phase complexed by the CPP. The nano-complexes form over a pH range from 5.0 to 9.0. Under neutral and alkaline conditions, the CPP stabilize calcium and phosphate ions, forming metastable solutions that are supersaturated with respect to the basic calcium phosphate phases. The amount of calcium and phosphate bound by CPP increases as pH rises, reaching the point where the CPP have bound their equivalent weights of calcium and phosphate. 
Mechanism of action
Casein phosphor-peptides are responsible for the high bioavailability of calcium from milk and other dairy products. CPP have the ability to bind and stabilize calcium and phosphate in solution, as well as to bind to dental plaque and tooth enamel. Calcium phosphate is normally insoluble that is, forms a crystalline structure at neutral pH. However, the CPP keeps the calcium and phosphate in an amorphous, noncrystalline state. In this amorphous state, calcium and phosphate ions can enter the tooth enamel. The high-concentration of calcium and phosphate ions in dental plaque have been extensively researched and proven to reduce the risk of enamel demineralization and promote remineralization of tooth enamel. ,,, CPP stabilize ACP, localize ACP in dental plaque, thereby maintaining a state of supersaturation with respect to tooth enamel, reducing demineralization and enhancing remineralization.  The CPPs have been shown to keep fluoride ions in solution, thereby enhancing the efficacy of the fluoride as a remineralizing agent. 
Evidence based studies
Bussadori et al.  conducted long-term and short-term cytotoxicity assessment of CPP-ACP paste in rat fibroblasts and concluded that CPP-ACP paste demonstrates low cytotoxicity in rat fibroblast culture.
Lozenges are also a suitable vehicle for the delivery of CPP-ACP to promote enamel remineralization was demonstrated by Cai et al.  Dentifrice containing calcium and phosphate ions has been found to increase the bioavailability of fluoride, resulting in increased uptake of fluoride in in vitro studies using enamel cores.  CPP-ACPF paste showed promising results as a remineralizing material when compared to acidulated phosphate fluoride gel and sodium fluoride varnish (NaF) for remineralization of artificially induced dental erosion in primary and permanent teeth.  Biomimetic approaches to the stabilization of bioavailable calcium, phosphate, and fluoride ions and the localization of these ions to noncavitated caries lesions for a controlled remineralization show promise for the noninvasive management of dental caries  [Table 1].Combining fluoride and ACP with CPP-ACP can give a synergistic effect on enamel remineralization was demonstrated using laser autofluorescence. ,, Also, CPP-ACP effectively decreases the lesion depth better than fluoridated toothpaste when compared to a nonfluoridated toothpaste.  Kumar et al.  concluded that CPP-ACP decreases lesion depth irrespective of whether or not it was used as a toothpaste or topical coating. For application in patients with orthodontic appliances, the effect of CPP-ACP on the load-deflection properties of beta-titanium wires was checked and was concluded that CPP-ACP did not have a statistically significant effect on the loading modulus of elasticity.  The effect of CPP-ACP paste on tooth mineralization was also checked using field emission scanning electron microscopy, and it was seen that CPP-ACP paste was effective in preventing demineralization of enamel and dentin more effectively than the placebo paste (CPP-ACP free).  Remineralization of enamel subsurface lesions by CPP-stabilized calcium phosphate solutions was checked by Reynolds.  The CPP, by stabilizing calcium phosphate in solution, maintain high-concentration gradients of calcium and phosphate ions and ion pairs into the subsurface lesion and thus effect high rates of enamel remineralization. The effects of an anticariogenic CPP on calcium diffusion in streptococcal model dental plaques was checked by Rose,  and it was concluded that CPP-ACP binds well to plaque, providing a large calcium reservoir within the plaque and slowing diffusion of free calcium. Shen et al.  checked remineralization of enamel subsurface lesions by sugar-free chewing gum containing CPP-ACP and found that the addition of CPP-ACP to either sorbitol- or xylitol-based gum resulted in a dose-related increase in enamel remineralization.
Shirahatti et al.  demonstrated that the use of nonfluoridated dentifrice and also the use of paste incorporated with CPP-ACP can reduce the progression in depths of enamel lesions when applied to early lesions. The resistance to the progression of lesion depth diminishes when the agents are applied to more progressed enamel lesions. Yimcharoen et al.  concluded from a study using polarized light microscopy that CPP-containing toothpaste, 260 ppm fluoride-containing toothpaste paste and a 500 ppm fluoride-containing toothpaste all had significant efficacy for inhibiting demineralization of carious lesions. However, 500 ppm fluoride-containing toothpaste inhibited lesion progression better than CPP-containing toothpaste and 260 ppm fluoride-containing toothpaste.
However, promising results were obtained using high calcium milk and CPP-ACP which enhanced remineralization of enamel erosion caused by chlorinated water. 
Commercially available MI Paste™ and MI Paste Plus™ series of products is based on Recaldent™ (CPP-ACP) technology since late 2002. MI Paste contains 10% of the CPP-ACP molecule by weight. MI Paste Plus has also been developed, which contains 900 parts/million (ppm) NaF (0.2%).  CPP-ACPF is <2 nanometers in size and can penetrate into biofilms and enamel.  These are widely used for the treatment of white spot lesions, during/after orthodontics, for areas of enamel which are hypomineralized, treatment of fluorosis after bleaching, improving the appearance of enamel, tooth sensitivity especially after in-office bleaching procedures, ultrasonic scaling, hand scaling or root planning,  erosion, dental erosion during pregnancy, protecting the very young, caries stabilization, root surface caries and patients with special needs.  The material is pH responsive, with increasing pH increasing the level of bound ACP and stabilizing free calcium and phosphate so that spontaneous precipitation of calcium phosphate does not occur. 
To conclude, there is extensive clinical as well as laboratory evidence for the effects of CPP-ACP as a remineralizing agent, with over 100 clinical studies since the 1980's, CPP-ACP technology has been proven to bind readily to pellicle, plaque, soft tissue and even HAP when applied within the oral cavity.  Also CPP-ACP can be safely and effectively administered by paste, mouthrinse, lozenges, chewing gum and tooth mousse.  All products being classified by the United States Food and Drug Administration (FDA) as generally recognized as safe. 
A2. Amorphous calcium phosphate
The ACP technology was developed by Dr. Ming S. Tung. In 1999, ACP was incorporated into toothpaste called Enamelon and later reintroduced in 2004 in Enamel Care toothpaste by Church and Dwight. The sources of calcium and phosphorous are two salts, calcium sulfate, and dipotassium phosphate. When the two salts are mixed, they rapidly form ACP that can precipitate onto the tooth surface.  ACP compounds are considered prime candidates for remineralization therapy due to their high solubility under oral conditions and ability to rapidly hydrolyze to form apatite.  However, many studies have found inconsistent results when ACP technology is used alone. ,, The fluoridating efficiency of the dual phase product significantly gets compromised during the sink life of the product.  The conventional NaF toothpaste provides significantly greater levels of remineralization and or/inhibition of demineralization than the new so-called "remineralizing toothpaste." ,
A3. Dicalcium phosphate dehydrate
Dicalcium phosphate dehydrate, CaHPO 4·2H 2 O; the chemically correct name is calcium hydrogen phosphate dihydrate; the mineral brushite (90)) can be easily crystallized from aqueous solutions at pH <6.5. DCPD is added to toothpaste both for caries protection (in this case, it is coupled with F-containing compounds such as NaF and/or Na 2 PO 3 F) and as a gentle polishing agent.  DCPD (brushit) and octacalcium phosphate (OCP) have been related as being precursors to the formation of apatite.  Artificial salivas often have a demineralizing potential or are neutral; only a few offer the potential for remineralization. The effects of various calcium and phosphate additions to a commercially available saliva substitute on remineralization of demineralized dentin were investigated  which found that modified saliva natura solutions slightly supersaturated with respect to DCPD and OCP are capable to remineralize dentin. The use of remineralizing artificial saliva (i.e., modified saliva natura) is a promising approach for dentate patients suffering from hyposalivation in their management of both dental caries and hyposalivation.  Many biological mineralization processes involve DCPD and OCP especially in supersaturated biological fluids such as serum and saliva.  Also the dissolution rates for DCPD, OCP and HAP crystals are invariably found to decrease even in undersaturation conditions.  Inclusion of DCPD in a dentifrice increases the levels of free calcium ions in plaque fluid, and these remain elevated for up to 12 h after brushing, when compared to conventional silica dentifrices.  Also, there is enhanced calcium incorporation into Enamel from DCPD, also increased levels are detected in plaque up to 18 h. 
Hydroxyapatite is the main constituent of the dental tissues representing in enamel and dentine the 95wt% and 75wt%, respectively.  HAP, as well as in bone, is responsible for the mechanical behavior of the dental tissues. Poorly crystalline HA nanocrystals, in addition to the excellent biological properties of HA, such as nontoxicity and lack of inflammatory and immunizer responses, have bioresorption properties under physiological conditions. This property can be modulated by modifying its degree of crystallinity, which is achieved by the implementation of innovative synthesis with a nanosize crystals control. , It has gained wide acceptance in medicine and dentistry in recent years.  Carbonated HAP nanocrystals synthesized with tailored biomimetic characteristics for composition, structure, size and morphology can chemically bind themselves on the surfaces of teeth hard tissues, filling the scratches, producing a bound biomimetic apatitic coating, protecting the enamel surface structure.  A concentration of 10% nano-hydroxyapatite (nHA) is considered to be optimal for remineralization of early enamel caries. ,,, Also nHA has the potential to remineralize erosive enamel lesions caused by exposure to soft beer.  Toothpastes containing n-HAp revealed higher remineralizing effects compared to amine fluoride toothpastes with bovine dentine.  An elevated Ca concentration in the remineralizing solution was also observed after a single treatment with the nHA dentifrice. 
A5. Bioactive Glass Materials
Bioactive glass is made of synthetic mineral containing sodium, calcium, phosphorous and silica (sodium calcium phospho silicate), which are all elements naturally found in the body.  Bioactive glass materials have been used in medicine and dentistry for years. This unique material has numerous novel features, including the ability to act as a biomimetic mineralizer, matching the body's own mineralizing traits, while also affecting cell signals in a way that benefits the restoration of tissue structure and function. Bioactive glass is considered a break-through advance in remineralization technology. 
Mechanism of action
When in contact with saliva or water, first releases sodium ions. This elevates the pH into the range essential for HAP formation (7.5-8.5). The calcium and phosphate are released to supplement the normal levels found in saliva. This increase in ionic concentration, combined with an increase in pH, causes the ions to precipitate onto the tooth surface and form calcium hydroxycarbonate apatite (HCA) to remineralize the defect and to occlude open tubules. The standard for Bioactive glass formulation is commonly known as 45S5, which has been used extensively in research studies. It contains 45 wt% SiO 2 , 24.5 wt% Na 2 O and Ca, O and 6 wt% P 2 O5 .  These particles have been shown to release ions and transform into HCA for up to 2 weeks. Ultimately, these particles will completely transform into HCA. 
Studies have been reported in literature which claim that bioglass dentifrices produce significantly more remineralization than Fluoride dentifrices. , Also adding bioglass (NovaMin ® ) to fluoride dentifrices significantly enhanced fluoride uptake into artificial carious lesions in enamel surfaces and provides a synergistic action.  Also, bioglass is capable of Tubule occlusion of root dentin as demonstrated by an in-vitro study. 
A commercial product based on this technology is The NovaMin R Technology, which was developed by Dr. Len Litkowski and Dr. Gary Hack.  This technology is claimed to be promising. 
Despite its name, Pronamel™ (GlaxoSmithKline, Middlesex, UK) is not considered a remineralizing agent per se, and it does not contain any calcium compounds. , The results of studies conducted show that pronamel reduces enamel erosion from acidic challenges from diet, fruit juices. ,, After treatment with the demineralizing solution followed by Pronamel, both interprismatic and prismatic enamel structures still appear evident. 
A7. Calcium carbonate carrier (SensiStat)
The SensiStat technology was developed by Dr. Israel Kleinberg of New York. The technology was first incorporated into Ortek's Proclude desensitizing Prophy Paste and later in Denclude.  A prime reaction is that the highly soluble arginine bicarbonate component of SensiStat surrounds, or is surrounded by, particles of the poorly soluble calcium carbonate component, and because of the adhesive properties of the composition forms a paste-like plug that not only fills the open tubules but also adheres to the dentinal tubule walls. Because of its alkalinity, the SensiStat also reacts with the calcium and phosphate ions of the dentinal fluid to make the plug chemically contiguous with the dentinal walls and, therefore, more secure. Subsequent testing of the plug by exposure to strong external acids has confirmed that it is firm. This composition has received US FDA approval (number K002989). 
To conclude, SensiStat can be used to treat early surface demineralizations, and halt development to frank caries that requires restoration.
A sugarless mint containing CaviStat ® (an arginine bicarbonate calcium carbonate complex) was tested for its capability of preventing the development of dental caries in the primary molars and first permanent molars. It was evident that mint confections containing CaviStat can inhibit both caries onset and caries progression, also CaviStat mint confection technology is a simple and economical means for reducing substantially one of the most prevalent diseases in these children. 
A9. Tricalcium phosphate
Tricalcium phosphate (TCP) is a new hybrid material created with a milling technique that fuses beta TCP and sodium lauryl sulfate or fumaric acid. When TCP comes into contact with the tooth surface and is moistened by saliva, the protective barrier breaks down making calcium, phosphate and fluoride ions available to the tooth.  TCP has also been considered as one possible means for enhancing the levels of calcium in plaque and saliva.  The remineralizing ingredient of the new product Clinpro 5000 toothpaste is TCP, which consists of calcium oxides, calcium phosphate, and free phosphates. This product contains a high-concentration (5000 ppm) of fluoride, which also aids in remineralization by attracting calcium and phosphate ions to the tooth's surface.1 Clinpro 5000 is applied as toothpaste and is not suitable for overnight use because of its high-fluoride concentration. 
Tricalcium phosphate with 950 ppm fluoride paste treatments increases the hardness of the teeth in vitro.  and also increased the surface microhardness of eroded enamel by chlorinated water in vitro.  Also TCP-Si (silica) - Ur (urea) can be combined with fluoride to produce anti-erosion benefits greater than those achieved with fluoride alone. 
A10. Trimetaphosphate ion
The potential mode of action of trimetaphosphate ion (TMP) is likely to involve in adsorption of the agent to the enamel surface, causing a barrier coating that is effective in preventing or retarding reactions of the crystal surface with its fluid environment, and hence reducing demineralization during acid challenge.  The effectiveness of TMP can be attributed to the fact that TMP assists the diffusion of calcium ions to the inner of enamel or reduced their loss to the solutions  also Biomimetic remineralization using sodium-TMP is a promising method to remineralize artificial carious lesions particularly in areas devoid of seed crystallites. 
The authors could find one study investigating the effect of silica and zirconia on the stability of bioactive ACP mineral. Hybrid ACP fillers, especially Zr-ACP, could be utilized in applications in which it is desired to enhance the performance of composites, sealants, and/or adhesives in preventing demineralization or actively promoting remineralization. 
A11. Biomimetically modified mineral trioxide aggregate
The remineralization efficacy of mineral trioxide aggregate (MTA) in phosphate-containing simulated body fluid by incorporating polyacrylic acid and sodium tripolyphosphate as biomimetic analogs of matrix proteins for remineralizing caries-like dentin was examined and was concluded that biomimetic analogs in modified MTA provides a potential delivery system for realization of the goal of biomimetic remineralization of dentin and widens the scope of MTA applications in dentistry because of release of biomimetic analogs from set MTA, Inclusion of polyphosphate in the MTA may serve as a supplementary phosphate source when its availability is compromised. 
A12. Sucrose-free polyol gum
The results of various studies and meta-analysis indicate that there is a statistically significant reduction in caries with the use of sucrose-free polyol gums compared with no gum chewing. 
Similarly there is a lot of evidence suggesting xylitol candy/lozenge/syrup, xylitol dentifrice, triclosan, iodine, topical chlorhexidine products like chlorhexidine varnish, chlorhexidine/thymol varnish, chlorhexidine mouthrinses, chlorhexidine gels and sialogogues have anti-caries effect and are capable of reversal of the carious process.
B. Those neutralising bacterial acids
Other strategies to combat demineralization include neutralizing bacterial acid using calcium carbonate as plaque pH buffering effect , and sodium bicarbonate to provide an alkaline oral environment.
Alternatively, calcium containing agents like calcium lactate, calcium glycerophosphate, and calcium phytate can be used. They act by increasing plaque calcium and phosphate levels.  Also, toothpastes containing chlorophyll, ammoniated toothpaste, and anti-enzyme pastes can be used. 
C. Antiplaque agents
Anti-microbials and antibiotics
A variety of antibiotics and antimicrobials are used to combat dental plaque. Many types of mouthrinse active ingredients have been evaluated for their plaque-reducing effectiveness and ability to reduce mutans streptococci, including chlorhexidine, essential oils, triclosan, cetylpyridinium chloride, sanquinarin, sodium dodecyl sulfate, and various metal ions (tin, zinc, copper).  Toxicity of many of these metals (e.g., aluminum, molybdenum, barium, and copper) restricts the concentration at which they could be safely used.  However, the evidence supporting the effectiveness of antiplaque agents in preventing dental caries, with the possible exception of chlorhexidine  and triclosan,  is very limited.
Chlorhexidine applied as a rinse partially reduces some bacteria but not others that are hiding within the biofilm. Better antibacterials and better delivery systems are needed. Xylitol delivered by gum or lozenge appears to be effective clinically in reducing cariogenic bacteria and caries levels, but novel systems that deliver therapeutic amounts when needed would be a major advance, especially for young children. Reducing the cariogenic bacterial challenge and enhancing the effect of fluoride by the use of new sustained delivery systems would have a major effect on dealing with caries as a disease. 
Discussing this section in detail is beyond the scope of this paper.
| Conclusion|| |
Evidence suggests that initial noncavitated lesions can be remineralized using appropriate technologies, both fluoride and nonfluoride based. Saliva plays an important role in the remineralization. Also, it is important that the control of caries be dealt with biofilm control. The nonfluoride remineralization strategies will be of benefit to many. Because of changes in dietary habits, lifestyle, and longer life expectancy, there is an increasing prevalence of enamel and dentin erosion, dental caries and other factors which affect the health of dental tissues. With these nontocic alternative remineralization strategies, we would be able to re-establish the health of oral tissues without being under the risk of fluoride toxicity if ingested at high levels, in particular in children.
| References|| |
Zero DT. Dentifrices, mouthwashes, and remineralization/caries arrestment strategies. BMC Oral Health 2006;6 Suppl 1:S9.
Wolff MS, Larson C. The cariogenic dental biofilm: Good, bad or just something to control? Braz Oral Res 2009;23 Suppl 1:31-8.
Stephan RM. Changes in hydrogen ion concentration on tooth surfaces and in carious lesions. J Am Dent Assoc 1940;27:718-23.
Bernie KM. Remineralization!Strategies:!! Advancements in Fluoride, Calcium & Phosphate Technologies. Available from: http://www.EducationalDesigns.com
. [Last accessed on 2012 Aug 12].
Meyer-Lueckel H, Schulte-Mönting J, Kielbassa AM. The effect of commercially available saliva substitutes on predemineralized bovine dentin in vitro
. Oral Dis 2002;8:192-8.
Alauddin SS. In vitro
remineralization of human enamel with bioactive glass containing dentifrice using confocal microscopy and nanoindentation analysis for early caries defense. A thesis, University of Florida; 2004. Available from: http://www.ufdc.ufl.edu/ufe0007162/00001
. [Last accessed on 2014 Aug 27].
Dowker SE, Anderson P, Elliot JC, Gao XJ. Crystal chemistry and dissolution of calcium phosphate in dental enamel. Mineral Mag 1999;63:791-800.
Liu Y, Li N, Qi Y, Niu LN, Elshafiy S, Mao J, et al
. The use of sodium trimetaphosphate as a biomimetic analog of matrix phosphoproteins for remineralization of artificial carieslike dentin. Dent Mater 2011;27: 465-77.
Bertassoni LE, Habelitz S, Marshall SJ, Marshall GW. Mechanical recovery of dentin following remineralization in vitro
- an indentation study. J Biomech 2011;44:176-81.
Bertassoni LE, Habelitz S, Pugach M, Soares PC, Marshall SJ, Marshall GW Jr. Evaluation of surface structural and mechanical changes following remineralization of dentin. Scanning 2010;32:312-9.
Dai L, Liu Y, Salameh Z, Khan S, Mao J, Pashley DH, et al.
Can Caries-Affected Dentin be Completely Remineralized by Guided Tissue Remineralization? Dent Hypotheses 2011;2:74-82.
Pradeep K, Kumar PR. Remineralizing agents in the non-invasive treatment of early carious lesions. Int J Dent Case Rep 2011;1:73-84.
Ferguson MM. The persistent dry mouth. Contin Med Educ N Z Fam Physician 2002;29:1-11.
Aguiar GP, Jham BC, Magalhães CS, Sensi LG, Freire AR. A review of the biological and clinical aspects of radiation caries. J Contemp Dent Pract 2009;10:83-9.
Badr SB, Ibrahim MA. Protective effect of three different fluoride pretreatments on artificially induced dental erosion in primary and permanent teeth. J Am Sci 2010;6:442-51.
Ranjitkar S, Kaidonis JA, Roger SJ. "Gastroesophageal Reflux Disease and Tooth Erosion," International Journal of Dentistry, vol. 2012, Article ID 479850, p. 10, 2012. doi:10.1155/2012/479850.
Karlinsey RL, Mackey AC, Walker ER, Frederick KE, Fowler CX. In vitro
evaluation of eroded enamel treated with fluoride and a prospective tricalcium phosphate agent. J Dent Oral Hygiene 2009;1:52-8.
Goswami M, Saha S, Chaitra TR. Latest developments in non-fluoridated remineralizing technologies. J Indian Soc Pedod Prev Dent 2012;30:2-6.
Chhabra KG, Shetty PJ, Prasad KVV, Mendon CS, Kalyanpur R. The beyond measures: Non flouride preventive measures for dental caries. J Int Oral Health 2011;3:1-8.
Al-Batayneh OB. The clinical applications of tooth moussetm and other CPP-ACP products in caries prevention: Evidence-based recommendations. Smile Dent J 2009;4:8-12.
Reynolds EC. Remineralization of enamel subsurface lesions by casein phosphopeptide-stabilized calcium phosphate solutions. J Dent Res 1997;76:1587-95.
Bussadori KS, Santos EM, Guedes CC, Motta LJ, Fernandes KPS, Mesquita-Ferrari RA, et al
. Cytotoxicity assessment of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) paste. Conscientiae Saúde 2010;9:354-9.
Cai F, Shen P, Morgan MV, Reynolds EC. Remineralization of enamel subsurface lesions in situ
by sugar-free lozenges containing casein phosphopeptide-amorphous calcium phosphate. Aust Dent J 2003;48:240-3.
Collins FM. Treatment options for tooth discoloration and remineralization. RDH 2008;28:1-11. doi: 02797720.
Cochrane NJ, Cai F, Huq NL, Burrow MF, Reynolds EC. New approaches to enhanced remineralization of tooth enamel. J Dent Res 2010;89:1187-97.
El Sayad I, Sakr AK, Badr YA. Combining casein phosphopeptide-amorphous calcium phosphate with fluoride: Synergistic remineralization potential of artificially demineralized enamel or not? J Biomed Optics 2009;14:044039.
Agnihotri Y, Pragada NL, Patri G, Thajuraj PK. The effect of CPP-ACP on remineralization of artificial caries like lesions: An In vitro
study. Indian J Multidiscip Dent 2011;2;366-9.
Kumar VL, Itthagarun A, King NM. The effect of casein phosphopeptide-amorphous calcium phosphate on remineralization of artificial caries-like lesions: An in vitro
study. Aust Dent J 2008;53:34-40. doi: 10.1111/j.1834-7819.2007.00006.x.
Massih K. The Effect Of Casein Phosphopeptide-Amorphous Calcium Phosphate On Load-Deflection Properties Of Beta-Titanium Wires Used In Orthodontics University Of Pittsburgh, School Of Dental Medicine; 2009. Available from: d-scholarship.pitt.edu/8077/1/MassihThesis2009.pdf. [Last accessed on 2014 Aug 26].
Oshiro M, Yamaguchi K, Takamizawa T, Inage H, Watanabe T, Irokawa A, et al.
Effect of CPP-ACP paste on tooth mineralization: An FE-SEM study. J Oral Sci 2007;49:115-20.
Rose RK. Effects of an anticariogenic casein phosphopeptide on calcium diffusion in streptococcal model dental plaques. Arch Oral Biol 2000;45:569-75.
Shen P, Cai F, Nowicki A, Vincent J, Reynolds EC. Remineralization of enamel subsurface lesions by sugar-free chewing gum containing casein phosphopeptide-amorphous calcium phosphate. J Dent Res 2001;80:2066-70.
Shirahatti RV, Ankola AV, Nagesh L, Hallikerimath S. The effects of three different pastes on enamel caries formation and lesion depth progression - An In Vitro
Study. J Oral Health Comm Dent 2007;1:1-6.
Yimcharoen V, Rirattanapong P, Kiatchallermwong W. The effect of casein phosphopeptide toothpaste versus fluoride toothpaste on remineralization of primary teeth enamel. Southeast Asian J Trop Med Public Health 2011;42:1032-40.
Vongsawan K, Surarit R, Rirattanapong P. The effect of high calcium milk and casein phosphopeptide-amorphous calcium phosphate on enamel erosion caused by cholinated water. Southeast Asian J Trop Med Public Health 2010;41:1494-9.
Zhao J, Liu Y, Sun WB, Zhang H. Amorphous calcium phosphate and its application in dentistry. Chem Cent J 2011;5:40.
Reynolds EC. Casein phosphopeptide - amorphous calcium phosphate and the remineralization of enamel. US Dentistry 2006:51-54.
Dorozhkin SV. Nanodimensional and nanocrystalline apatites and other calcium orthophosphates in biomedical engineering, biology and medicine. Materials 2009;2:1975-2045.
Tschoppe P, Kielbassa AM, Lueckel HM. Evaluation of the remineralising capacities of modified saliva substitutes in vitro
. Arch Oral Biol 2009;54:810-6.
Lynch RJ, Churchley D, Butler A, Kearns S, Thomas GV, Badrock TC, et al.
Effects of zinc and fluoride on the remineralisation of artificial carious lesions under simulated plaque fluid conditions. Caries Res 2011;45:313-22.
George HN. The involvement of calcium phosphates in biological mineralization and demineralization processes. Pure Appl Chem 1992;64:1673-8.
Sullivan RJ, Masters J, Cantore R, Roberson A, Petrou I, Stranick M, et al.
Development of an enhanced anticaries efficacy dual component dentifrice containing sodium fluoride and dicalcium phosphate dihydrate. Am J Dent 2001;14:3A-11.
Roveri N, Battistella E, Bianchi CL, et al
., "Surface Enamel Remineralization: Biomimetic Apatite Nanocrystals and Fluoride Ions Different Effects," Journal of Nanomaterials 2009, Article ID 746383 doi:10.1155/2009/746383.
Roveri N, Battistella E, Foltran I, Foresti E, Iafisco M, Lelli M, et al
. Synthetic biomimetic carbonate-hydroxyapatite nanocrystals for enamel remineralization. Adv Mater Res Vols 2008;47:821-4.
Tschoppe P, Zandim DL, Martus P, Kielbassa AM. Enamel and dentine remineralization by nano-hydroxyapatite toothpastes. J Dent 2011;39:430-7.
Roveri N, Foresti E, Lelli M, Lesci IG. Recent advancements in preventing teeth health hazard: The daily use of hydroxyapatite instead of fluoride. Recent Pat Biomed Eng 2009;2:197-215.
Huang SB, Gao SS, Yu HY. Effect of nano-hydroxyapatite concentration on remineralization of initial enamel lesion in vitro
. Biomed Mater 2009;4:034104.
King NM, Itthagarun A, Cheung M. Remineralization by nanohydroxyapatite-containing dentifrice: A pH cycling study using slurry. J Dent Res 2006;85:000-000.
Itthagarun A, King NM, Cheung M. Remineralization effects of nanohydroxyapatite-containing dentifrice: A pH-cycling study using supernatant. J Dent Res 2006;85:000-000.
Najibfard K, Karthikeyan R, Chedjieu I, Amaechi BT. In Situ
Remineralization of Early Caries Lesions by Nano-hydroxyapatite Dentifrice. 88 th
General Session & Exhibition of the IADR 2010. p. 14-17.
Haghgoo R, Abbasi F, Rezvani MB. Evaluation of the effect of nanohydroxyapatite on erosive lesions of the enamel of permanent teeth following exposure to soft beer in vitro
. Sci Res Essays 2011;6:5933-6.
Nakashima S, Yoshie M, Sano H, Bahar A. Effect of a test dentifrice containing nano-sized calcium carbonate on remineralization of enamel lesions in vitro
. J Oral Sci 2009;51:69-77.
Madan N, Madan N, Sharma V, Pardal D, Madan N. Tooth remineralization using bio-active glass - A novel approach. J Acad Adv Dent Res 2011;2:45-50.
Vahid Golpayegani M, Sohrabi A, Biria M, Ansari G. Remineralization Effect of Topical NovaMin Versus Sodium Fluoride (1.1%) on Caries-Like Lesions in Permanent Teeth. J Dent (Tehran) 2012;9:68-75.
Stone AH, Schemehorn BR, Burwell AK. Enhanced enamel fluoride uptake from NovaMin® - Containing fluoride dentifrices. J Dent Res 2008;87:0625.
Wefel JS. NovaMin: Likely clinical success. Adv Dent Res 2009;21:40-3.
Mason SC. New In Vitro
and In Situ
evidence for a toothpaste formulated for those at risk from erosive tooth wear. J Clin Dent 2009;20:175-7.
Jaidka S, Somani R, Khaira S, Jaidka R. The Effect of prevident and pronamel in the prevention of chemical erosion: A comparative study. Indian J Stomatol 2012;3:102-5.
Poggio C, Lombardini M, Colombo M, Bianchi S. Impact of two toothpastes on repairing enamel erosion produced by a soft drink: An AFM in vitro
study. J Dent 2010;38:868-74.
Acevedo AM, Montero M, Sanchez FR. Clinical evaluation of the ability of CaviStat® in a mint confection to inhibit the development of dental caries in children. J Clin Dent 2008;19:1-8.
Rirattanapong P, Vongsavan K, Tepvichaisillapakul M. Effect of five different dental products on surface hardness of enamel exposed to chlorinated water in vitro
. Southeast Asian J Trop Med Public Health 2011;42:1293-8.
Su N, Marek CL, Ching V, Grushka M. Caries prevention for patients with dry mouth. J Can Dent Assoc 2011;77:b85.
Rirattanapong P, et al
. Effect of various forms of calcium in dental products on human enamel microhardness in vitro
. Southeast Asian J Trop Med Public Health 2011;42:1056.
Karlinsey RL, Mackey AC, Stookey GK. In vitro
remineralization efficacy of NaF systems containing unique forms of calcium. Am J Dent 2009;22:185-8.
Delbem AC, Bergamaschi M, Rodrigues E, Sassaki KT, Vieira AE, Missel EM. Anticaries effect of dentifrices with calcium citrate and sodium trimetaphosphate. J Appl Oral Sci 2010;20:94-8.
Skrtic D, Antonucci JM, Eanes ED, Brunworth RT. Silica- and zirconia-hybridized amorphous calcium phosphate: Effect on transformation to hydroxyapatite. J Biomed Mater Res 2002;59:597-604.
Qi YP, Li N, Niu LN, Primus CM, Ling JQ, Pashley DH, et al.
Remineralization of artificial dentinal caries lesions by biomimetically modified mineral trioxide aggregate. Acta Biomater 2012;8:836-42.
Rethman MP, Beltrán-Aguilar ED, Billings RJ, Burne RA, Clark M, Donly KJ, et al
. Non-fluoride caries preventive agents. Full report of a systematic review and evidence-based recommendations. ADA Center for Evidence Based Dentistry; 2011. Available from: http://www.ada.org
› ADA News › Media Resources › Press Releases. [Last accessed on 2012 Jul 25].
Yamamotoa O, Ohiraa T, Alvareza K, Fukudab M. Antibacterial characteristics of CaCO3-MgO composites. Mater Sci Eng 2010;B173:208-12.
Featherstone JD. Delivery challenges for fluoride, chlorhexidine and xylitol. BMC Oral Health 2006;6 Suppl 1:S8.
[Figure 1], [Figure 2]